The present invention relates to a pharmaceutical composition useful for topical application to an eye for treatment or prevention of infective disease of the eye. In particular, the present invention relates to an ophthalmic formulation of an oxazolidinone antibiotic that can be applied to the eye for treatment or prevention of ophthalmic infection by a gram-positive bacterial agent. The field of the present invention also includes therapeutic or prophylactic use of such a formulation, and use of such a formulation in preparation of a medicament.
Numerous oxazolidinone compounds have been reported having therapeutically and/or prophylactically useful antibiotic, in particular antibacterial, effect. Among such compounds are those illustratively disclosed in the following patents, each of which is individually incorporated herein by reference.
U.S. Pat. No. 5,164,510 to Brickner.
U.S. Pat. No. 5,231,188 to Brickner.
U.S. Pat. No. 5,565,571 to Barbachyn and Brickner.
U.S. Pat. No. 5,627,181 to Riedl et al.
U.S. Pat. No. 5,652,238 to Barbachyn et al.
U.S. Pat. No. 5,688,792 to Barbachyn et al.
U.S. Pat. No. 5,698,574 to Riedl et al.
U.S. Pat. No. 6,069,145 to Betts.
Compounds disclosed in above-cited U.S. Pat. No. 5,688,792 include for example the compound (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, also referred to herein as linezolid. Linezolid has the structure shown in formula (I): 
and is in commercial use as a medicament under the trademark Zyvox(copyright) of Pharmacia Corporation. Linezolid exhibits strong antibacterial activity against gram-positive organisms including those of the following genera: Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis), Streptococcus (e.g., Streptococcus viridans, Streptococcus pneumoniae), Enterococcus, Bacillus, Corynebacterium, Chlamydia and Neisseria. Many such gram-positive organisms have developed significant levels of resistance to other antibiotics. About 65% of all cases of bacterial keratitis and about 85% of all cases of bacterial conjunctivitis are attributable to infection by gram-positive organisms such as those listed above.
Above-cited U.S. Pat. No. 5,688,792 discloses that the subject antibiotic oxazolidinone compounds, including linezolid, can be formulated as a gel or cream for topical application to skin.
International Patent Publication No. WO 00/03710, incorporated herein by reference, discloses a method of treating bacterial keratitis or bacterial conjunctivitis in an eye, comprising topical administration of an oxazolidinone antibiotic to the infected eye. Preferred oxazolidinone compounds for use according to the method of WO 00/03710 include (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (linezolid) and (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]lphenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (eperezolid). The oxazolidinone compound is said to be administered in a formulation such as a solution, cream, ointment, emulsion, suspension or slow release formulation, a solution being preferred. Formulations exemplified include 10% and 12% weight/volume solutions of linezolid. It is suggested that the formulation be administered 2-4 times daily for 7-10 days or until the infection is gone, and that preferably about 1 drop to about 5 drops of the formulation are administered each time. It is further disclosed in WO 00/03710 that the oxazolidinone compound can be used individually, in combination with another oxazolidinone compound, in combination with other antibacterial agents, or in combination with non-antibacterial agents.
International Patent Publication No. WO 00/18387, incorporated herein by reference, discloses ophthalmic compositions comprising an oxazolidinone antimicrobial agent. Preferred oxazolidinone compounds according to WO 00/18387 are those of above-cited U.S. Pat. No. 5,627,181. Optionally the compositions can further comprise an anti-inflammatory agent. Typically 1-4 drops of a solution or suspension, or a comparable amount of an ointment, gel or other solid or semisolid composition, are said to be applied 1-4 times a day.
A challenge for topical administration of drugs to the eye is a high rate of drug loss from the exterior of the eye. Only a small volume of fluid can be accommodated in the exterior of the eye, including the conjunctival sac, and under normal conditions lacrimal fluid fills most of the available volume. The additional volume of fluid in the form of a drug formulation that can be accepted by a human eye without washout varies from about 3 xcexcl to about 25 xcexcl, but is normally about 10 xcexcl. Furthermore, turnover rate of lacrimal fluid is high, typically about 16% per minute, and this can lead to rapid loss of an instilled drug by normal lacrimal drainage. Thus under normal conditions, only about 10% to about 20% of a drug dose is retained in the exterior of the eye 5 minutes after placement therein of 1-2 drops of a solution or suspension composition of the drug, and the composition is almost completely eliminated within 15 minutes. See for example Sorensen and Jensen (1979), Acta Ophthalmol. (Copenhagen) 57, 564-581. Reflex blinking and lacrimation caused by irritation from the topical administration can result in even faster drug loss.
Increasing viscosity of the instilled formulation and hence of the lacrimal fluid can reduce the rate of lacrimal drainage and thereby increase residence time of the drug in the exterior of the eye. Ointments are often used for this reason; however, ointments often cause discomfort by interfering with vision and free movement of the eyelids. Clear aqueous solutions and suspensions are therefore usually a preferred choice, especially for daytime administration.
U.S. Pat. No. 3,867,519 to Michaels, incorporated herein by reference, discloses a device for delivering a drug at a controlled rate to an eye, the device comprising an inner reservoir of the drug confined in a biodegradable matrix and an outer bioerodible membrane through which the drug passes into the eye.
U.S. Pat. No. 3,914,402 to Shell, incorporated herein by reference, discloses an ophthalmic dosage form comprising solid particles of a drug enclosed within a bioerodible polymer such as a polyester, cross-linked gelatin or a polycarboxylic acid. The polymer is said to gradually erode in the eye, releasing the drug at a controlled rate.
U.S. Pat. No. 3,960,150 to Hussain et al., incorporated herein by reference, discloses a bioerodible ocular insert containing a drug. Through erosion of the ocular insert in the eye, the drug is said to be released at a controlled rate.
U.S. Pat. No. 3,963,025 to Whitaker and Gad, incorporated herein by reference, discloses a bioerodible ocular drug delivery device said to have improved retention in an eye.
U.S. Pat. No. 4,014,335 to Arnold, incorporated herein by reference, discloses an ocular drug delivery device comprising a shaped body having a drug reservoir enclosed by walls, one of which is formed of a material that is permeable to the drug and controls the release rate of the drug.
U.S. Pat. No. 4,057,619 to Higuchi and Hussain, incorporated herein by reference, discloses an ocular drug delivery system comprising an ethylene-vinyl ester copolymer through which a drug can diffuse.
U.S. Pat. No. 4,186,184 to Zaffaroni, incorporated herein by reference, discloses an ocular drug delivery system that can be inserted in an eye and that has a drug-releasing portal which can be oriented towards a preselected tissue of the eye for controlled release of the drug thereto.
U.S. Pat. No. 4,474,751 to Haslam et al., incorporated herein by reference, discloses liquid aqueous ophthalmic compositions comprising a drug, preferably a water-soluble drug, together with 10% to 50% by weight of a thermosetting polymer that forms a gel at a human body temperature. Upon placement of such a liquid composition in an eye, a gel is said to form thereby retarding loss of the drug from the eye by lacrimal drainage. Such compositions are said to be useful for ophthalmic delivery of antibacterial agents, for example vancomycin.
U.S. Pat. No. 4,861,760 to Mazuel and Friteyre, incorporated herein by reference, discloses a liquid in situ gelling composition said to be suitable for ophthalmic use. The composition contains in aqueous solution a polysaccharide that undergoes liquid-gel phase transition in response to ionic strength of tear fluid. A suitable polysaccharide is gellan gum, which can be used in a concentration of 0.1% to 2% by weight of the composition. Such a composition is said to be useful for ophthalmic delivery of antibacterial agents, for example vancomycin.
U.S. Pat. No. 5,192,535 to Davis et al., incorporated herein by reference, discloses liquid compositions said to be suitable for use as eye drops, utilizing a different in situ gelling mechanism. These compositions contain a lightly cross-linked carboxyl-containing polymer such as polycarbophil and have a pH of about 3.0 to about 6.5. Upon placement of such a composition in an eye, contact with lacrimal fluid having a pH of about 7.2 to about 7.4 is said to result in gelling and consequent increase of residence time in the eye, permitting sustained release of a drug contained in the composition. Drugs for which such a composition is said to be useful include antibiotics, for example vancomycin.
U.S. Pat. No. 5,212,162 to Missel et al., incorporated herein by reference, discloses further liquid in situ gelling compositions said to be suitable for ophthalmic use. The compositions contain a drug together with a finely-divided (conveniently about 1 to about 25 xcexcm particle size) carrier that binds with the drug, and a gelling polysaccharide, preferably a carrageenan, especially a carrageenan having not more than 1.0 sulfate moiety per disaccharide unit, e.g., eucheuma carrageenan, kappa-carrageenan or furcellaran. Such compositions are said to be useful for ophthalmic delivery of anti-infective agents, for example ciprofloxacin.
U.S. Pat. No. 5,403,841 to Lang et al., incorporated herein by reference, discloses further liquid in situ gelling compositions said to be suitable for ophthalmic use. These compositions contain a carrageenan having not more than 1.0 sulfate moiety per disaccharide unit that is capable of gelling in 0.5% to 1.0% aqueous sodium chloride solution. Such compositions are said to be useful for ophthalmic delivery of anti-infective agents, for example ciprofloxacin.
U.S. Pat. No. 5,587,175 to Viegas et al., incorporated herein by reference, discloses further liquid in situ gelling compositions said to be suitable for ophthalmic use. These compositions contain an ionic polysaccharide, for example gellan gum, alginate gum or chitosan, and a film-forming agent, for example hydroxypropyl methylcellulose, carboxymethylcellulose, sodium chondroitin sulfate, sodium hyaluronate, polyvinylpyrrolidone, etc. The compositions are pH buffered to match pH of tear fluid. Gelling is said to occur upon contact with calcium ions. Such compositions are said to be useful for ophthalmic delivery of antibacterial agents, for example vancomycin.
U.S. Pat. No. 5,869,079 to Wong and Kochinke, incorporated herein by reference, discloses a biodegradable ocular implant comprising a hydrophobic entity such as a lactic/glycolic acid polyester and a hydrophilic entity such as hydroxypropylmethylcellulose, this combination of entities being said to modulate each other""s release and that of a drug contained therewithin.
U.S. Pat. No. 5,876,744 to Della Valle et al., incorporated herein by reference, discloses bioadhesive and mucoadhesive compositions, including some said to be useful as ophthalmic compositions, comprising mixtures of synthetic polymers such as polycarbophil and polyvinyl alcohol and biopolymers such as alginic acid, hyaluronic acid and dermatan sulfate. Such compositions are said to be capable of increasing contact time with a treated eye of specific drugs.
European Patent No. 0 424 043, incorporated herein by reference, discloses a liquid ophthalmic composition comprising a sulfated polysaccharide or derivative thereof that undergoes a liquid-gel transition on interaction with proteins of the lacrimal fluid in the eye. Such sulfated polysaccharides are said to include kappa-carrageenan, iota-carrageenan and mixtures thereof. The composition is said to be useful for ophthalmic delivery of antibacterial agents.
None of the references cited above specifically contemplates formulating an oxazolidinone antibiotic in a composition exhibiting prolonged residence time in a treated eye. None of the references cited above specifically contemplates such a composition further comprising a preservative. None of the references cited above leads one of skill in the art to expect a problem in preparing such a composition that does not contain solid particulates, or to find a solution to such a problem. None of the references cited above specifically contemplates a combination therapy or coformulation of an oxazolidinone antibacterial agent having a high degree of activity against gram-positive bacteria with one or more antibacterial agents effective against gram-negative bacteria.
A need remains for a composition of an oxazolidinone antibiotic drug suitable for topically treating and/or preventing bacterial infections of the eye, that delivers the drug continuously to the eye over a prolonged period of time, for example over at least about 2 hours, preferably longer. A particular need remains for such a composition further comprising a preservative. A further particular need remains for such a composition that is substantially free of solid particulates that could cause discomfort and/or irritation to a treated eye. Furthermore, a need remains for an ophthalmically acceptable co-therapy or coformulation that is effective against both gram-negative organisms and gram-positive organisms, particularly gram-positive organisms that have become resistant to most antibiotics.
One or more of these needs will be seen to be met by the invention now described.
The present invention provides a pharmaceutical composition suitable for topical administration to an eye, the composition comprising as active agent one or more oxazolidinone antibacterial drugs in a concentration effective for treatment and/or prophylaxis of a gram-positive bacterial infection of one or more tissues of the eye, and one or more ophthalmically acceptable excipient ingredients that reduce rate of removal of the composition from the eye by lacrimation such that the composition has an effective residence time in the eye of about 2 to about 24 hours.
Lacrimation is the production of tear fluid, and can remove matter from the eyes both by external wash-out and by lacrimal drainage into the nasopharyngeal cavity via the nasolacrimal ducts. A consequence of removal of an ophthalmic composition from a treated eye is a reduced concentration of the active agent in the lacrimal fluid and hence in the target tissue.
For sustained antibacterial action, the concentration in the lacrimal fluid and in the target tissue, e.g., the conjunctiva or the cornea, must remain above the MIC90 for the active agent in question. The MIC90 is the minimum inhibitory concentration for 90% of the target organisms, in this instance infective gram-positive bacteria. For example, where the active agent is linezolid, the MIC90 is about 4 xcexcg/ml. By xe2x80x9ceffective residence timexe2x80x9d herein is meant a period of time following application of the composition to the eye during which the concentration of the active agent in the lacrimal fluid and/or in the target tissue remains above the MIC90 for that active agent.
The composition therefore provides sustained antibacterial action over a period of at least about 2 hours.
The invention also provides a method of preparing a medicament for treating or preventing a gram-positive bacterial infection in an eye, using a composition as described above.
Also embraced by the present invention is a method of treating or preventing a gram-positive bacterial infection in an eye, the method comprising application to the eye of a composition as described above in a therapeutically or prophylactically effective dose.
Furthermore, the present invention provides a method of treating or preventing both gram-positive and gram-negative bacterial infections in an eye, the method comprising topical application to the eye in co-therapy (including coformulation) one or more oxazolidinone antibiotics and one or more antibiotics effective against gram-negative organisms. xe2x80x9cCo-therapyxe2x80x9d herein means administration topically to the eye, at the same time or sequentially, of an ophthalmically acceptable composition of the oxazolidinone(s) and a separate ophthalmically acceptable composition of the gram-negative effective antibiotic(s), in a treatment regimen intended to provide a beneficial effect from co-action of the two types of antibiotic. xe2x80x9cCoformulationxe2x80x9d herein means that the oxazolidinone(s) and the gram-negative effective antibiotic(s) are administered topically to the eye as components of a single ophthalmically acceptable composition.
In one embodiment of the invention, a composition as described herein is used topically in treatment of an existing bacterial infection. Infective diseases of the eye for which compositions and methods of the invention are useful include without limitation conjunctivitis, keratitis, blepharitis, blepharoconjunctivitis, orbital and preseptal cellulitis and endophthalmitis. In preferred methods the infected tissue is one that is directly bathed by the lacrimal fluid, as in conjunctivitis, keratitis, blepharitis and blepharoconjunctivitis.
In infective diseases of the eye where the causal organism is non-bacterial, there can be benefit in prophylactic use of a composition of the invention to control secondary bacterial infections. Examples of such situations include conjunctivitis and keratitis of viral etiology, e.g., adenoviral conjunctivitis, molluscum contagiosum, herpes simplex conjunctivitis and keratitis, etc., and fungal keratitis.
Prophylactic uses of a composition of the invention also include post-traumatic prophylaxis, especially post-surgical prophylaxis, and prophylaxis prior to ocular surgery.
What constitutes a xe2x80x9cconcentration effective for treatment and/or prophylaxis of a gram-positive bacterial infectionxe2x80x9d depends, among other factors, on the particular oxazolidinone compound or compounds being administered; the residence time provided by the particular formulation of the active agent; the species, age and body weight of the subject; the particular ophthalmic condition for which treatment or prophylaxis is sought; and the severity of the condition. In the case of linezolid, an effective concentration in a composition of the invention for topical administration to an eye will generally be found in the range from about 0.01% to about 20%, more typically about 0.05% to about 8%, weight/volume. For oxazolidinone compounds other than linezolid, an appropriate concentration range is one that is therapeutically equivalent to the linezolid concentration range indicated above.
A composition of the invention is conveniently but not necessarily formulated as an in situ gellable aqueous liquid, and can be administered as eye drops. Typically each drop, generated by a conventional dispensing means, has a volume of about 10 to about 40 xcexcl. From 1 to about 6 such drops typically provides a suitable dose of the oxazolidinone active agent. Where the composition is administered in a form other than eye drops, for example as an ophthalmic ointment or as a solid implant, an equivalent dose is provided. Such a dose can be administered as needed, but typically administration to the eye 1 to about 6 times per day, in most cases 2 to 4 times a day, provides adequate continuing relief or prevention of the infective disease indicated.
The term xe2x80x9cophthalmically acceptablexe2x80x9d with respect to a formulation, composition or ingredient herein means having no persistent detrimental effect on the treated eye or the functioning thereof, or on the general health of the subject being treated. It will be recognized that transient effects such as minor irritation or a xe2x80x9cstingingxe2x80x9d sensation are common with topical ophthalmic administration of drugs and the existence of such transient effects is not inconsistent with the formulation, composition or ingredient in question being xe2x80x9cophthalmically acceptablexe2x80x9d as herein defined. However, preferred formulations, compositions and ingredients are those that cause no substantial detrimental effect, even of a transient nature.
Contemplated compositions are highly effective in treating gram-positive bacterial infections of the eye. Without being bound by theory, it is believed that the prolonged residence time exhibited by compositions of the invention is responsible at least in part for their superior effectiveness. In a topical administration method as provided by the present invention, the dosage of the active agent is generally much lower than would typically be administered orally to provide a therapeutically or prophylactically effective blood serum concentration.
The concentration of the active agent in an ophthalmic composition of the invention can also be much lower than that exemplified for a topically applied simple solution formulation of an oxazolidinone antibiotic. For example, above-cited International Patent Publication No. WO 00/03710 discloses in Example 6 thereof a treatment for bacterial keratitis, wherein a 10% (100 mg/ml) solution of linezolid is dropped on the surface of the eye in an amount of 3-5 drops, 4 times a day; and in Example 7 thereof a treatment for bacterial conjunctivitis, wherein a 12% (120 mg/ml) solution of linezolid is dropped on the surface of the eye in an amount of 3 drops, 3 times a day. By contrast, a preferred composition of the present invention can be effective at a linezolid concentration of about 0.5 to about 80 mg/ml, more preferably about 0.5 to about 50 mg/ml, still more preferably about 0.5 to about 20 mg/ml, and most preferably about 0.5 to about 10 mg/ml, for example about 2 to about 2.5 mg/ml.
The very low dose permitted by the composition and method of the invention is a major advantage of the invention. Topical application as herein described, with greatly reduced drainage via the nasolacrimal duct into the gastrointestinal tract, avoids unnecessary systemic distribution of the oxazolidinone antibiotic throughout the body, and thereby reduces risk of development of resistant strains of gram-positive bacteria.
Other features and advantages of the invention will be in part apparent and in part pointed out hereinafter.